Method and apparatus for intraocular brachytherapy

ABSTRACT

A method for performing intraocular brachytherapy and an apparatus for performing the same is disclosed. The apparatus preferably comprises a hand-held delivery device that advances a radiation source into an associated cannula or probe that is positioned adjacent the target tissue. The handpiece provides for shielded storage of the radiation source when retracted from the cannula and includes a slider mechanism for advancing and retracting the radiation source. The radiation source is mounted to a wire that has a flexible distal end and a relatively stiffer proximal end. A positioning system for the cannula is also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/544,001, filed Feb. 12, 2004.

The present invention relates to apparatus, systems and methods forperforming intraocular brachytherapy. The invention may be employed inthe treatment of a variety of eye disorders, but is particularly suitedfor treatment of macular degeneration in which neovascularized oculartissue is treated by means a of local, directional delivery of aradiation dose emitted by a radioactive source to target tissues.

BACKGROUND

The slow, progressive loss of central vision is known as maculardegeneration. Macular degeneration affects the macula, a small portionof the retina. The retina is a fine layer of light-sensing nerve cellsthat covers the inside back portion of the eye. The macula is thecentral, posterior part of the retina and contains the largestconcentration of photoreceptors. The macula is typically 5 to 6 mm indiameter, and its central portion is known as the fovea. While all partsof the retina contribute to sight, the macula provides the sharp,central vision that is required to see objects clearly and for dailyactivities including reading and driving.

Macular degeneration is generally caused by age (termed Age RelatedMacular Degeneration or “AMD”) or poor circulation in the eyes. Smokersand individuals with circulatory problems have an increased risk fordeveloping the condition. AMD is the leading cause of blindness inpeople older than 50 years in developed countries. Between the ages of52-64, approximately 2% of the population are affected. This rises to anastounding 28% of the population over the age of 75.

There are two forms of macular degeneration, which are known as “wet”and “dry” macular degeneration. Dry macular degeneration blurs thecentral vision slowly over time. Individuals with this form of maculardegeneration may experience a dimming or distortion of vision that isparticularly noticeable when trying to read. In dry maculardegeneration, yellowish deposits called drusen develop beneath themacula. Drusen are accumulations of fatty deposits, and most individualsolder than 50 years have at least one small druse. These fatty depositsare usually carried away by blood vessels that transport nutrients tothe retina. However, this process is diminished in macular degenerationand the deposits build up. Dry macular degeneration may also result whenthe layer of light-sensitive cells in the macula become thinner as cellsbreak down over time. Generally, a person with the dry form of maculardegeneration in one eye eventually develops visual problems in botheyes. However, dry macular degeneration rarely causes total loss ofreading vision.

Wet macular degeneration (which is the neovascular form of the disease)is more severe than dry macular degeneration. The loss of vision due towet macular degeneration also comes much more quickly than dry maculardegeneration. In this form of the disease, unwanted new blood vesselsgrow beneath the macula (Choroidal Neo-Vascularization (CNV) endothelialcells). These choroidal blood vessels are fragile and leak fluid andblood, which causes separation of tissues and damages light sensitivecells in the retina. Individuals with this form of macular degenerationtypically experience noticeable distortion of vision such as, forexample, seeing straight lines as wavy, and seeing blank spots in theirfield of vision.

Early diagnosis of the wet form of macular degeneration is vital. If theleakage and bleeding from the choroidal blood vessels is allowed tocontinue, much of the nerve tissue in the macula may be killed ordamaged. Such damage cannot be repaired because the nerve cells of themacula do not grow back once they have been destroyed. While wet AMDcomprises only about 20% of the total AMD cases, it is responsible forapproximately 90% of vision loss attributable to AMD.

It has been proposed to provide a device that is particularly suitablefor the localized delivery of radiation for the treatment of maculardegeneration. See, U.S. Pub. Appln. US 2002/0115902A1 to DeJuan, et al.,which is incorporated herein by reference. A localized retinaldetachment (called a “bleb”) is created by performing a retinotomy andinjecting saline therethrough using a subretinal infusion needle, thuscreating a space between the partially-detached retina and the area ofchloridal neo-vascularization. A radiation-emitting source is introducedinto the bleb and the CNV is directly irradiated. The exposure of thenew blood vessels formed during the wet form of macular degeneration toradiation provides sufficient disruption of the cellular structures ofthe new blood cell lesions to reverse, prevent, or minimize theprogression of the macular degeneration disease process. Such therapycan potentially restore visual acuity, extend retention of visual acuityor slow the progressive loss of visual acuity.

The present application relates to advances in apparatus, systems andmethods for performing intraocular brachytherapy, in general, and forthe treatment of macular degeneration with radiation, in particular.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partial longitudinal cross-sectional view of an apparatusfor performing intraocular brachytherapy comprising a handpiece, acannula secured to the handpiece, and a radiation source wire (“RSW”)interior of the handpiece and cannula in a retracted position.

FIG. 2 is a cross-sectional view of the apparatus of FIG. 1 with theradiation-emitting element advanced to the treatment position.

FIG. 3 is a top view (as compared to FIGS. 1 and 2) of a portion of thehousing comprising part of handpiece shown in FIG. 1.

FIG. 4 is an enlarged view of the cannula associated with the system ofFIG. 1, in partial cross-section.

FIG. 5 is a fragmentary, cross-sectional view of the radioactive sourcewire forming a portion of the system shown in FIG. 1.

FIG. 6 is a perspective view of the distal end of the cannula and a doseflattening filter comprising a portion of the tip or distal end of thecannula.

FIG. 7 is an exploded perspective view of a first embodiment of apositioning system for use with the system of FIG. 1.

FIGS. 8 and 9 illustrate the use of the positioning system of FIG. 7 inconnection with the system of FIG. 1.

FIG. 10 is an enlarged view showing the treatment of CNV with the deviceof FIG. 1.

FIG. 11 shows the dose rate profile at the treatment side of thedelivery device.

FIG. 12 is a schematic view of a further version of the cannula for usein the present invention having an inflatable balloon at its distal end.

FIG. 13 is a schematic view of an alternate embodiment of the cannula ofFIG. 1 including retractable wires for properly spacing the treatmentend of the cannula and the radioactive source from the target tissue.

FIG. 14 is a schematic view of an alternate version of the cannula inwhich a retractable wire basket is provided for maintaining the properspacing of the radiation source with respect to the target tissue.

FIG. 15 is a schematic view of a further embodiment of the cannula foruse with the present invention in which the cannula includes a lumen forinjecting and withdrawing various fluids at the location of the distalend of the cannula.

FIG. 16 is a cross-sectional view of the cannula of FIG. 15.

FIG. 17 is a schematic view of a further embodiment of the cannula foruse in connection with the present invention in which the non-treatmentside of the distal end of the catheter is relieved to minimize contactwith the retina.

DETAILED DESCRIPTION

In the sub-retinal treatment of AMD, vitreoretinal surgical techniquesare used to facilitate placement of a radioactive source thatpreferably, but not exclusively, emits beta or other ionizing radiationtemporarily in a subretinal space by means of an intraocular cannula,sheath or probe. Other non-ionizing radiation sources, such as light orheat sources, as circumstances require, may also be used.

In accordance with one aspect of the present invention, an apparatus isprovided employing the radioactive source and a delivery device thatpermits movement of the source between a stored position and treatingposition. When in the stored (retracted) position, the radiation sourceis surrounded by a suitable material, such as a stainless steel and leadlining, that effectively protects the surgeon and patient duringhandling and initial positioning. During treatment, the source ispreferably located within a specially designed tip of platinum iridium(Pt/Ir), or other suitable material, that provides for directionaladministration of the radiation with controlled intensity, whileshielding and protecting the retina and other surrounding non-targettissues.

With reference to FIGS. 1 and 2, the system, generally designated 10,includes two main components: a radiation source, which may be locatedat the distal end of a source wire (RSW) 12 and a delivery device 14that comprises, in the illustrated embodiment, a handle 16 and adelivery cannula 18 (also called a sheath or probe). In addition, apositioning system 20, shown in FIG. 7, and method, illustrated in FIGS.8 and 9, are provided to assist in the precise positioning of the devicewithin the eye.

Radiation source is broadly defined herein, and is not limited toionizing radiation, light radiation, or heat radiation. For example, theradiation source is intended to include a treatment source of any of avariety of treatment regimens, including ionizing radiation. Theradiation source for the RSW 12 comprises any suitable radiation source,including radioactive materials such as gamma and beta emitters, x-ray(e.g., miniaturized x-ray generators), and non-ionizing radiationsources, such as laser or other light sources. Alternatively,ultrasound, heat, cryo-ablation, or microwave sources may also beutilized.

Preferably, an essentially beta emitting material, such as aStrontium/Yttrium 90 (Sr-90/Y-90) beta emitting isotope is used. With asource activity of approximately 11 mCi and a location of about 1-3 mmfrom the target tissue (preferably about 1-1.5 mm), the treatmentduration is relatively short, approximately 2-4 minutes. The system andmethod provide for sub-retinal delivery of radiation at the site of thechoroidal neovascularization that occurs in macular degeneration, orother treatment site. When employing ionizing radiation, the systempreferably provides radiation to a target site at a dose rate of fromapproximately 4 to 20 GY/min; with a preferred target dose of betweenapproximately 10 and 40 GY, with the target dose more preferably beingapproximately 26 GY for neovascularized tissue.

As illustrated in FIG. 5, the preferred embodiment of the radiationsource includes a cylindrical aluminum insert 22 that is doped with theSr-90/Y-90 isotope in accordance with conventional techniques andpreferably resides inside a sealed stainless steel canister. Thecanister comprises a seed tubing 24 sealed on its distal end with a lid26 and on its proximal end with a lid 28. The stainless steel canistermay be mounted to a solid or braided wire made of stainless steel (orother material) to form the RSW 12 that is used to advance the source toand retract the source from the treatment location.

As shown in FIG. 5, the radioactive source wire 12 preferably includes arelatively flexible distal or leading strand 30 and a relatively stifferproximal or handle strand 32. Specifically, the flexibility of theleading strand 30 is such as to allow unimpeded mechanical transportthrough the cannula 18 around a radius of curvature of from 4 to 8 mm.The RSW 12 has an overall length on the order of 190 mm, which providesa 10mm-15 mm protrusion of the wire from the rear of the handle 16 (asseen in FIGS. 1 and 2) when the RSW 12 is advanced to the treatmentposition, thus providing for removal or repositioning of the RSW, ifnecessary.

The distal end of the leading strand 30 includes a connection tubing 34closed by a lid 36 for facilitating attachment of the canister housingthe radioactive insert 22. A further connection tubing 38 is used tojoin the proximal end of the leading strand 30 to the distal end of thehandle strand 32. In the illustrated embodiment, the leading strand 30has a smaller outside diameter than the handle strand. Thus, theproximal end of the leading strand 30 carries an additional length oftubing 40 to build up the outside diameter of the leading strand 30 tomatch that of the handle strand. The proximal end of the handle strand32 also includes a length of tubing 41 for reinforcement. Other than theradioactive insert 22, the various components of the RSW 12 arepreferably made of stainless steel and are joined together by laserwelding. Other means for delivering and/or retrieving the radioactivesource, as disclosed in the prior art, may also be used. For example,the radioactive source may not be secured to a wire, and movement of thesource between treatment and storage positions can be accomplishedpneumatically or hydraulically. See, e.g., U.S. Pat. No. 5,683,345,which is incorporated herein by reference.

The delivery device 14 is preferably, but not necessarily, handheld tofacilitate control and positioning of the delivery cannula 18 duringuse. When not in use, the radiation source 22, e.g., a beta radiationsource, may be positioned inside the shielded storage handle 16. Thehandle 16 includes a slider mechanism to which a proximal portion of theRSW 12 is secured, the slide mechanism being moveable between treatmentposition (FIG. 2), in which the radioactive source 22 is positioned atthe distal end of the cannula 18, and a retracted position (FIG. 1) forstorage of the radioactive source 22 within the handle 16. While in thestorage position, the radiation source is preferably shielded by acombination of stainless steel (inner shield) and lead (outer shield).The stainless steel shield blocks the beta radiation, while the leadshield reduces the secondary radiation (known as brehmsstrahlung). Othersuitable materials may also be used for shielding.

With reference to FIGS. 1-3, the handle 16 comprises a multi-parthousing with an elongated cylindrical case 42 closed at its proximal endby end cap 44 and at its distal end by a central hub 46, to which thecannula 18 is secured. The hub 46 is preferably made of stainless steeland serves as the inner radiation shield for the radioactive source whenin the storage position. The wall thickness of the shielding portion ofthe hub is approximately 1.9 mm. The hub 46 also carries the lead outershield, designated 48, which has a wall thickness of approximately 4.6mm. The hub 46 and outer shield 48 are carried by a cup-like member 50that is secured to the distal end of the case 42.

As noted above, the handle 16 includes an advancement or positioningmechanism (also referred to as a slider mechanism), generally designated52, for moving the radioactive source 22 between the storage andtreatment positions. The slider mechanism 52 includes a carrier member54 that is slidingly received on the interior of the cylindrical case 42of the handle 16. The carrier 54 includes a central aperture, throughwhich the handle strand 32 of the RSW 12 extends, with the RSW 12 beingsecured to the carrier 54 by means of a set screw 56.

For moving the carrier 54 between the proximal and distal ends of thecase 42, an actuator pin 58 that extends through an elongated slot 60 inthe case 42 is secured to the carrier 54. As illustrated, the slot 60lies in a plane defined by the curved cannula 18, thus having the sameorientation as the cannula curve. The slot 60 permits approximately 60mm, or less, of travel for the carrier 54 and includes offsets 62, 64 atits distal and proximal ends, respectively, for receiving the actuatorpin 58, thus providing positive visual and tactile indications of theradioactive source 22 being located in the treatment and storagepositions. The proximal side of the carrier 54 also includes a coilspring 66 secured thereto by screw 68 for biasing the actuator pin intoa locked condition within proximal offset 64 when in the retractedposition.

With reference to FIG. 4, the intraocular probe 18 is preferably anintegral part of the delivery device, and is fabricated of a rigidmaterial, such as stainless steel. The probe, or cannula, in theillustrated embodiment, comprises a single lumen and is sealed at thedistal end to prevent contact between the radiation source and thepatient or the patient's bodily fluids. More particularly, the distalend of the probe includes an inner sleeve 70 (best seen in FIG. 6) inwhich the radiation source is located when in the treatment position.The inner sleeve 70 is configured to provide a desired dose profile,which is discussed in greater detail below. The inner sleeve 70 isreceived in a cover sleeve 72 that serves to seal the inner sleeve 70and also provides some radiation attenuation.

The distal end of the cannula 18 is curved or bent at an angle tofacilitate proper alignment of the radiation source and the treatmentarea. The tip 74 of the probe 18 also preferably has a rounded wedgeshape to facilitate positioning of the distal end under the retina, whenthe retina is partially detached and raised to form a “bleb” (as byinjection of saline or other liquid under the retina) during theperformance of the method.

The treatment side of the tip includes a molded, machined or otherwiseformed window 76 (sealed by the cover sleeve 72) that allows fordirectional administration of radiation. The window 76 is subdividedinto four smaller windows by longitudinal and transverse splines 77 thatintersect at centrally located solid area 79 that acts as a flatteningfilter to reduce the peak radiation from the source 22 received bytissue closest to the radiation source. As a result, the tissue to beirradiated at the treatment site receives a more uniform dosage. Thisflattening effect is shown in FIG. 11, which plots the dose rate (inGY/min) as a function of radial and axial distance from the radiationsource center. As can be seen in FIG. 11, the peak dose rate isgenerally flat at the center of the source, and decreases essentiallylinearly as the distance from the center increases. Various structuresof the flattening filter are discussed in the co-pending PCT application“Radioactive Radiation Source for Ophthalmic Brachytherapy,”PCT/EP2004/012415, filed Nov. 3, 2004, which is incorporated herein byreference. In general, the flattening filter preferably comprises ashield of selected thickness and/or material suspended in the window atthe point closest the treatment site that attenuates or blocks a portionof the radiation from escaping the probe.

A first embodiment of a system 20 for precise positioning of the probe18 is shown in FIG. 7. The positioning system 20 comprises a base 80 andcontact extension 82 which serve as a reference member and are adaptedto be mounted to the extra-ocular portion of the sheath or probe 18.Using the sclera (the surface of the eye) as a dimensional referencepoint or surface, a spring 84 is located on the probe 18 to provide apositive engagement of the contact extension 80 (when carried on thebase 82) against the sclera during initial placement. See FIGS. 8 and 9.

For purposes of assembly onto the probe, the base 80 has a slot 86 sizedto fit over the probe 18 so that it can be placed thereon. The contactextension 82 also has a slot 88 thereon to facilitate placement on theprobe 18 distally of the base 80. The contact extension 82 designed toseat on the base 80 and is maintained in position thereon by frictionalengagement. A handle 90 is provided that has a threaded end 92 that isreceived in a complimentarily-threaded aperture 94 in the base 80. Thethreaded end 92 of the handle 90 serves as a set screw to secure thebase 80 in position on the probe 18 after initial placement, as will bediscussed in greater detail below. The positioning system 78 may be madeof any suitable material, but is preferably made of acetal.

With reference to FIG. 8, the probe is initially positioned, with thetip 74 of the probe in light contact with the target area to beirradiated, touching either the retina or the CNV tissue under theretina. The spring 84 pushes the contact extension 82 mounted on thebase 80 into contact with the sclera. The handle 90 is then turned toengage against the probe 18, thus locking the base 80 into position onthe probe 18. The probe 18 is then withdrawn from the eye. With the base80 locked in position on the probe, a spacer 96, which also has a slot98 that permits it to be placed on the probe 18, is then placed betweenthe base 80 and the contact extension 82, as seen in FIG. 9, toaccurately set the distance between the treatment area and the probe tip74.

In practice, the spacer 96 has a thickness of from about 0.5 to 3 mm,and preferably 1-1.5 mm (more preferably 1 mm), so as to create a spaceof the same distance between the tip 74 of the probe 18 and the targetarea. The particular spacing may vary with the eye disorder treated, theradiation source being used, and the size of the treatment area. Aspacing of 1-2 mm (and preferably 1.5 mm) is the anticipated spacing fortreating the neovascularized tissue associated with macular degenerationwith a beta radiation source as described earlier. During the radiationdelivery, the contact extension rests against the sclera, resisting orpreventing further axial movement of the delivery device into the eye.

Alternatively, positioning of the probe tip can be facilitated by theuse of intra-ocular ultrasound or doppler measurement of the distancesbetween the distal end of the cannula and the target tissue. In suchcases, the distal end of the cannula may include an ultrasound ordoppler transducer (communicating with a read-out device) to bothtransmit and receive ultrasound or doppler waves. The data generatedthereby is analyzed in real time, and a calculated measurement of thedistance is presented on an optical readout or indicator. In a similarmanner, optical interferometry devices and techniques can be employedfor measuring the distance between the cannula tip and the targettissue.

Structures for assuring the proper spacing of the probe tip from thetarget site can take other forms. For example, as shown in FIG. 12, thetip of the probe 18 may include one or more balloons 100 that areinflatable upon locating the probe tip under the retina (R) in the blebto insure for spacing of the probe tip between the retina and treatmentzone. In addition, or alternatively, the distal end 101 of the probe 18can be at an angle with respect to the axis of the probe where theradioactive source is located when in the treatment position (againshown in FIG. 12—see also FIGS. 15 and 17). The angled distal end 101insures that a pre-determined minimum distance is maintained between theradioactive source and the target tissue.

In a second alternative, shown in FIG. 13, a preformed wire, or seriesof wires 102, are extendable from a lumen 104 in the probe to properlyspace or bump-off the probe tip from the treatment zone when advancedout of the lumen. A further alternative, shown in FIG. 14, is to use aretractable wire basket 106 that is advanced through a lumen 104 in theprobe when the probe is placed at the treatment site. A still furtheralternative is to secure a optic fiber to the probe that extends beyondthe distal end an amount corresponding to the desired spacing. When theoptic fiber contacts the target tissue, the fiber darkens, thus alertingthe surgeon to the desired spacing.

The basic procedure for sub-retinal intraocular brachytherapy accordingto the present invention is accomplished through standard vitrectomy andretinal detachment techniques, with the basic steps as follows. Prior totreatment, the surgeon confirms the location of the target tissue usingretinal vascular landmarks and identifies the preferred location of thesclerotomy entry point (i.e., temporal, nasal, etc.) in order to limitexposure of the fovea during treatment. The surgeon will also want toconfirm that the radiation source is properly positioned in the probe,when advanced to the treatment position. A device for testing for theproper positioning of the radiation source, and the method of its use,is disclosed in the co-pending PCT application, “Test Device for TestingPositioning of a Radioactive Source and Method of Using Same,”PCT/EP2004/012416, filed Nov. 3, 2004, which is herein incorporated byreference.

Then the subject is prepared pursuant to standard vitrectomy procedures.Specifically, the pupil of the subject is dilated and the patient ispositioned ventrally on the operating table. After appropriate cardiacand respiratory monitoring is established, and appropriate anesthesia isinduced, the eye is anesthetized, such as with a retrobulbar orperibulbar anesthesia.

Next, the treatment area is accessed. A speculum is placed to secure theeye lid, and surgery begins with a conjunctival incision into thesuperotemporal, superonasal and inferotemporal quadrants of the eye tobe treated. A scleral incision is made approximately 3 to 4 mm away fromthe surgical limbus in the inferotemporal quadrant, and an infusioncannula is inserted into the vitreous cavity. After confirming that theinfusion cannula is positioned properly, the infusion line is opened anda second and third scleratomy are created 3 to 4 mm away from thesurgical limbus in locations determined prior to commencement of thesurgery in the superonasal quadrant. An appropriate lens forvitreoretinal surgery is positioned and a vitrectomy performed, astandard endoilluminator being used to illuminate the vitreous cavity.

Next, the treatment probe is positioned. To this end, the spring 84 ofthe positioning system 20 is carefully slid over the probe 18 up to thedevice handle 16, and the positioning system is placed on to the probeshaft without the spacer element 96. See FIG. 8. The sclerotomy isextended to a length of approximately 1.3 mm, and the delivery probe isinserted through the sclerotomy incision into the vitreous cavity.

Under microscopic visualization, the surgeon places the tip of the probedirectly above the macula. Specifically, the probe is positioned bygently touching the retinal tissue, while directly holding the probecenter marker (a mark on the probe tip designating the center of theradiation source) above the center of the CNV complex. While the surgeonholds the probe steady at this position, the positioning system (base 80and contact extension 82) without the spacer 96 is secured onto theexternal portion of the delivery probe while in contact with the sclerato identify the precise location of the probe as it contacts the retinaby tightening the handle, and the cannula is removed from the vitreouscavity. The spacer 96 is then placed between the positioning system base80 and the contact extension 82, as shown in FIG. 9.

A localized retinal detachment (the “bleb”) is created by using asub-retinal infusion needle in the macular region, the bleb includingthe area of choroidal neovascularization. A new retinotomy is created onthe temporal edge of the bleb, with the new incision created less than 4mm away from the fovea to reduce the risk of a peripheral retinal tear.The retinotomy is approximately 1.3 mm in diameter in order toaccommodate the probe. The delivery device probe 18 is then reinsertedinto the vitreous cavity and into the sub-retinal space through thesecond retinotomy, as seen in FIG. 10. The distal end of the probe ispositioned directly above the center of the CNV complex with thepositioning system touching the sclera, thus insuring the distance ofthe probe tip is about 1.5 mm above the target area.

Next, the radiation dose is delivered to the target tissue. To this end,the radiation source is advanced by pushing the slider mechanism towardsthe tip of the probe. Once advanced, the source wire is locked intoposition by locating the pin in the detent 62. After the appropriatetreatment time, the slider mechanism is retracted to bring theradioactive source back to the storage and locked position. Afterinsuring that the radioactive source has been fully retracted into itsstorage position, the delivery probe is removed from the bleb andwithdrawn from the eye.

After removal of the probe, the retina is then reattachedintraoperatively, and a complete fluid-air exchange is performed,resulting in an air or gas tamponade in the vitreous cavity. Theretinotomy is closed by, e.g., laser photocoagulation, if necessary,while the superior sclerotomy is closed with ophthalmic sutured. Theinferotemporal sclerotomy is closed, and the conjunctiva is sutured withappropriate ophthalmic sutures. A mixture of antibiotics and steroidsmay then be administered in the sub-conjuctival space.

In an alternate method, the retina and other non-target tissue duringtreatment may be shielded and protected by introducing aradiation-attenuating fluid into the bleb that is created by lifting theretina away from the CNV. The fluid can consist of saline, or a fluidwith higher attenuation coefficient, such as contrast media. The use ofa radiation-attenuating fluid to protect non-target tissue may also beadvantageous during epi-retinal and epi-scleral applications ofradiation. In such cases, the radiation-attenuating fluid is merelyintroduced into the interior of the eye, rather than into thesub-retinal space.

Maintaining the bleb shape during the course of the procedure is alsoimportant to minimizing the potential for damage to the photoreceptors.It is contemplated that the bleb shape may be maintained in severaldifferent ways. For example, the bleb shape may be maintained byinjecting a high viscosity material into the sub-retinal space createdby the bleb. Because of the material's high viscosity, its ability toflow through the retinotomy is reduced. The high viscosity material isremoved, after treatment, using a standard vitrectomy device. Onesuitable high density material is a sodium hyaluronate preparation forophthalmic use sold by Pharmacia Company, under the trademark HEALON®. Asubstance with variable viscosity having a high initial viscosity duringthe treatment time, with a lower viscosity thereafter, would furtherfacilitate the removal of the material form the sub-retinal space uponcompletion of the procedure. A gelatinous substance whose viscosity canbe reduced through the administration of a diluting agent (e.g., water),a chemical agent (for adjusting ph), a temperature-charging agent orenergy, photo reaction due to light administration, etc., would besuitable.

Other methods for maintaining the bleb shape include applying a sealingsubstance (such as HEALON®) to the retinotomy and the probe/cannulainserted therethrough to prevent the bleb from deflating by blocking theescape of fluid between the probe and the retinotomy. An inflationagent, such as saline, can also be continuously introduced into thesub-retinal space with a small positive pressure by means of an openlumen 108 associated with the cannula 18 (FIGS. 15, 16). Further, thedistal end of the cannula can be provided with a balloon (FIG. 12) thatis inflated after the distal end of the cannula is introduced into thebleb in order to support the bleb and prevent the bleb from deflating orcollapsing.

The potential for damage to the photoreceptors by the probe may also beminimized if the cannula has a low-friction surface. This can beprovided by coating the probe with a lubricant or other coating, such asTeflon or electrolytic carbon, or providing the cannula with ahighly-polished surface, as by electro-polishing. Alternatively, thebackside 110 of the probe (i.e., the non-treatment side) can berelieved, as shown in FIG. 17, to lessen the degree of contact of theprobe with the photoreceptors.

The prevention or limiting of bleeding from the retina into thesub-retinal space, and the removal of any residual blood that shouldform therein, is also important for protecting the photoreceptors. Inthis regard, the area of the incision resulting from the vitrectomyperformed to create the bleb may be cauterized to prevent or limitretinal bleeding. Such cauterization may be achieved by diathermy,cryopexy, or the application of laser or RF energy using instrumentationand methods known for re-attaching the retina to the retinal pigmentepithelium in the case of retinal detachment.

Additionally, or alternatively, blood coagulants, such as antihemophilicFactor VIII (recombinant) (available from Bayer Healthcare as Kogenate),aminocaproic acid (available form Immunex as Amicar), and desmopressinacetate (available from Rhone Poulanc Rorer as Octostim), may also beinjected into the sub-retinal space to limit bleeding by means of theseparate lumen associated with the treatment device, as shown in FIGS.15, 16. The coagulant may also be removed through the same lumen.Injection of an iron-binding substance (such as apotransferrin) into theblood may also be used in facilitating the removal of blood from thesub-retinal space and preventing its oxidation.

After the CNV has been irradiated, an anti-proliferating drug(anti-Vascular Endothelial Growth Factor or anti-VEGF agent, such aspegaptanib sodium) may be injected into the sub-retinal space to preventand/or limit further growth of the CNV.

It has been observed that hypoxic cells seem to recover better fromradiation than healthy cells. Thus, it is believed that it would bebeneficial to reduce the retinal blood supply of the non-target tissueduring radiation treatment in order to facilitate the recovery of suchtissue after being subjected to radiation. To this end, it is proposedthat the tip of the probe include an inflatable balloon that causespressure on the retina when inflated to reduce the blood flow thereto,the radiation treatment being performed through the balloon.Alternatively, it is proposed to protect the non-target tissue with adeployable mask made of a radiation-blocking material that will bedeployed and located over the non-target tissue, while leaving thetarget tissue exposed. Such a material could be carried by the tip ofprobe 18 or by a separate device and deployed after formation of thebleb. The material could be biodegradable if desired.

The sub-retinal approach as described above, while believed to beeffective in treating AMD, requires an extremely high degree of skill onthe part of the ophthalmic surgeon to create the bleb and locate thetreatment cannula in the sub-retinal region. Accordingly, the deliverydevice of the present invention may also be used in methods forintraocular, epi-retinal application of radiation, in which no bleb iscreated.

Performance of the epi-retinal method is substantially easier then thesub-retinal approach. Intraocular access made simply through asclerotomy, and the distal end of the probe is located over the macula.No detachment of the retina or the creation of a bleb is required.Accurate placement of the probe may be accomplished by any of thepositioning systems described. Ultrasound or Doppler techniques known inthe art may also be used. Other mechanical methods may also be used,such as putting a stand-off fiber or “whisker” on the tip of the probethat touches the retina when the probe is properly positioned.Alternatively, an inflatable balloon that, when inflated, spaces theprobe the desired distance from the target tissue can also be used.

In a further alternative, a miniature radiation sensor that can beremotely interrogated may be placed on the retinal surface, and thedistance between the probe tip and the surface of the retina can bedetermined based upon the level of radiation measured by the sensor. Ifmultiple (i.e. 3) sensors are used, triangulation of the measuredradiation intensity would provide an accurate measurement of position.If multiple (i.e. 3) sensors are used, triangulation of the measuredradiation intensity would provide an accurate measurement of position.If at least three miniature event counters or sensors are positioned inan array on the periphery of the retina equidistant from the targettissue, the intensity/frequency of events measured by each point can beanalyzed and then compared. The position of source then can bedetermined through well-known three-dimensional triangulationcalculations at the beginning of the radiation administration. The eventcounters/sensors can be placed either in the eye, behind the eye, oreven on the front surface of the eye, if the radiation source produced asufficient emission to be measured externally. Alternatively, theradiation source can carry a small transducer on its tip that would emita “ping” that can be picked up by receivers positioned as describedabove. Other signaling/receiving systems such as light or RF can also beused. As a further method, a permanent magnet disposed on the tip of thedevice could produce a sufficient Galvanic effect in appropriate sensorsto be measurable, especially in an epi-retinal application where thesize constraints of the device are less critical. A digitally-enclosedsignal would provide improved speed and accuracy.

It will be understood that the embodiments and methods of the presentinvention that have been described are illustrative of the applicationof the principles of the present invention. Numerous modifications maybe made by those skilled in the art without departing from the truespirit and scope of the invention, including combinations of thefeatures that are individually disclosed or claimed herein.

1. A method for delivering radiation to a target tissue in an eye fromthe interior of the eye with a radiation delivery device having anelongated probe associated therewith, the probe having a distal endthrough which radiation can be selectively administered to the targettissue, the method comprising: creating an access to the interior of theeye through a surface of the eye; introducing the probe into theinterior of the eye through the access; positioning the distal end ofthe probe a predetermined distance from the target tissue; protectingnon-target tissue from radiation emitted from the distal end of theprobe; delivering a dose of radiation to the target tissue, includingattenuating the peak radiation dose delivered by the probe to the targettissue closest to the distal tip of the probe.
 2. The method of claim 1wherein the non-target tissue is protected by shielding structureassociated with the distal tip of the probe.
 3. The method of claim 1wherein the non-target tissue is protected by introducing a radiationattenuating fluid into the interior of the eye.
 4. The method of claim 1wherein the non-target tissue is protected by deploying a mask of aradiation-blocking material over the non-target tissue.
 5. The method ofclaim 1 wherein the target tissue comprises choroidal neovascularization (CNV) associated with macular degeneration, and theradiation dose is delivered to the target tissue epi-retinally.
 6. Themethod of claim 1 wherein the target tissue comprises choroidal neovascularization (CNV) associated with macular degeneration, and theradiation dose is delivered to the target tissue sub-retinally.
 7. Themethod of claim 6 further comprising: detaching a portion of the retinafrom the target tissue to form a bleb; maintaining the bleb by injectinga high viscosity fluid into the sub-retinal space; and after exposingthe sub-retinal region to radiation, removing the high viscosity fluidfrom the bleb.
 8. The method of claim 6 further comprising: detaching aportion of the retina from the target tissue to form a bleb by means ofretinotomy; introducing saline into the bleb; and maintaining the blebby applying a sealing substance to one or both of the probe and theretinotomy.
 9. The method of claim 6 further comprising: detaching aportion of retina from the target tissue by forming a bleb; andmaintaining the bleb by periodically injecting an inflation agent. 10.The method of claim 9 in which the inflation agent comprises saline. 11.The method of claim 6 further comprising: detaching a portion of theretina from the target tissue by means of a retinotomy to form a bleb;and cauterizing the retinotomy.
 12. The method of claim 6 furthercomprising: detaching a portion of the retina from the target tissue toform a bleb; injecting an anticoagulant into the bleb; and afterexposing the sub-retinal region to radiation, removing the anticoagulantfrom the bleb.
 13. The method of claim 6 further comprising: detaching aportion of the retina from the target tissue to form a bleb; and afterexposing the target tissue to radiation, introducing anantiproliferating agent into the bleb.
 14. The method of claim 6further: providing the distal end of the probe with an inflatableballoon; detaching the retina from the target tissue by forming a blebto provide direct access to the target tissue; introducing the distalend of the probe into the bleb; inflating the balloon to space thedistal end of the probe from the detached retina and the target tissueand to maintain the bleb.
 15. The method of claim 6 further comprising:providing the probe with a lumen having an opening at the distal end ofthe probe in which an elongated wire is slidingly received, the wirehaving a distal end that is moveable in and out of the distal end of theprobe and having a structure on the distal end thereof that expands asthe distal end of the wire is advanced out the distal end of the lumen;detaching the retina from the target tissue by forming a bleb to providedirect access to the target tissue; introducing the distal of the probeand lumen into the bleb; advancing the distal end of the wire out of thelumen so that the structure at the distal end thereof expands to spacethe probe from the target tissue.
 16. A method of treating target tissuebelow the retina of the eye, comprising: separating a portion of theretina from target tissue therebelow; injecting a radiation attenuatingmaterial between the retina and the target tissue; introducing aradiation source between the retina and target tissue; and exposing thetarget tissue to radiation from the radiation source.
 17. The method ofclaim 46 including restricting flow of radiation attenuating materialfrom between the retina and target tissue.
 18. A method of treatingtarget tissue below the retina of the eye, comprising: injecting aradiation attenuating material into the interior of the eye; positioninga radiation source in proximity to target tissue; and exposing thetarget tissue to radiation from the radiation source.
 19. The method ofclaim 18 wherein the radiation source is positioned epi-sclerally. 20.The method of claim 18 wherein the radiation source is positionedepi-retinally.